Obesity is a worldwide health challenge occurring at alarming levels in the United States and other developed nations. About 97 million adults in the United States are overweight. Of these 40 million are obese. Obesity and overweight greatly increase the risk of many diseases. Hypertension; type 2 diabetes; dyslipidemia; coronary heart disease; stroke; gallbladder disease; osteoarthritis; sleep apnea and other respiratory problems; and endometrial, breast, prostate, and colon cancers have been associated with higher body weights. Persons with higher body weights also suffer from a higher all-cause death rate. According to the National Institutes of Health about 280,000 adult deaths in the United States each year may be attributed in part to obesity.
Weight loss is desirable in the case of obesity and overweight individuals. Weight loss can help to prevent many of these harmful consequences, particularly with respect to diabetes and cardiovascular disease (CVD). Weight loss may also reduce blood pressure in both overweight hypertensive and non-hypertensive individuals; serum triglycerides levels and increases the beneficial high-density lipoprotein (HDL)-form of cholesterol. Weight loss also generally reduces somewhat the total serum cholesterol and low-density lipoprotein (LDL)-cholesterol levels. Weight loss may also reduce blood glucose levels in overweight and obese persons.
While weight loss is desirable, it is hard to achieve. Many treatments for the management of overweight and obesity and the maintenance of weight loss exist. However, recidivism is rampant. Approximately, 40 percent of women and 24 percent of men are trying to actively lose weight at any given time. These treatments include low-calorie diets and low-fat diets; increased physical exercise; behavioral therapies directed toward reducing food intake, pharmacotherapy; surgery; and combinations of the above.
The pharmacopoea of weight loss is relatively bare. Drugs such as sibutramine, dexfenfluramine, orlistat, phenylpropanolamine, phenteramine, or fenfluramine can facilitate weight loss in obese adults when used for prolonged periods. In general, however, the safety of long-term administration of pharmaco-therapeutic weight loss agents is unknown. For instance, recently due to concerns about valvular heart disease observed in patients, fenfluramine and dexfenfluramine have been withdrawn from the market. In the face of the slim pharmacopoea and the high prevalence of obesity and overweight, there is a need for new pharmaceutical methods and compositions to promote and maintain weight loss.
Fatty acid ethanolamides (FAE) are unusual components of animal and plant lipids, and their concentrations in non-stimulated cells are generally low (Bachur et al., J. Biol. Chem., 240:1019-1024 (1965); Schmid et al., Chem. Phys. Lipids, 80:133-142 (1996); Chapman, K. D., Chem. Phys. Lipids, 108:22 1-229 (2000)). FAE biosynthesis can be rapidly enhanced, however, in response to a wide variety of physiological and pathological stimuli, including exposure to fungal pathogens in tobacco cells (Chapman et al., Plant Physiol., 116:1163-1168 (1998)), activation of neurotransmitter receptors in rat brain neurons (Di Marzo et al., Nature, 372:686-691 (1994); Giuffrida et al., Nat. Neurosci., 2:358-363 (1999)) and exposure to metabolic stressors in mouse epidermal cells (Berdyshev et al., Biochem. J., 346:369-374 (2000)). The mechanism underlying stimulus -dependent FAE generation in mammalian tissues is thought to involve two concerted biochemical reactions: cleavage of the membrane phospholipid, N-acyl phosphatidylethanolamine (NAPE), catalyzed by an unknown phospholipase D; and NAPE synthesis, catalyzed by a calcium ion- and cyclic AMP-regulated N-acyltransferase (NAT) activity (Di Marzo et al., Nature, 372:686-691 (1994); Cadas et al., J. NeuroSci., 6:3934-3942 (1996); Cadas et al., H., J. Neurosci., 17:1226-1242 (1997)).
The fact that both plant and animal cells release FAEs in a stimulus-dependent manner suggests that these compounds may play important roles in cell-to-cell communication. Further support for this idea comes from the discovery that the polyunsaturated FAE, anandamide (arachidonylethanolamide), is an endogenous ligand for cannabinoid receptors (Devane et al., Science, 258:1946-1949 (1992))-G protein-coupled receptors expressed in neurons and immune cells, which recognize the marijuana constituent Δ9-tetrahydrocannabinol (Δ9-THC) (for review, see reference (Pertwee, R. G., Exp. Opin. Invest. Drugs, 9:1553-1571 (2000)).
Two observations make it unlikely that other FAEs also participate in cannabinoid neurotransmission. The FAE family is comprised for the most part of saturated and monounsaturated species, such as palmitylethanolamide and oleoylethanolamide, which do not significantly interact with cannabinoid receptors (Devane et al., Science, 258:1946-1949 (1992); Griffin et al., J. Pharmacol. Exp. Ther., 292:886-894. (2000)). Second, when the pharmacological properties of the FAEs have been investigated in some detail, as is the case with palmitylethanolamide, such properties have been found to differ from those of Δ9-THC and to be independent of activation of known cannabinoid receptor subtypes (Calignano et al., Nature, 394:277-281 (1998)). Thus, the biological significance of the FAEs remains elusive.
Oleoylethanolamide (OEA) is a natural analogue of the endogenous cannabinoid anandamide. Like anandamide, OEA is produced in cells in a stimulus-dependent manner and is rapidly eliminated by enzymatic hydrolysis, suggesting a role in cellular signaling. However, unlike anandamide, OEA does not activate cannabinoid receptors and its biological functions were here-to-fore essentially unknown.
There is a need for additional methods and agents to treat obesity and overweight as well as to maintain weight loss. The present invention meets this need by providing novel methods and pharmaceutical compositions related to our instant discovery that oleoylethanolamide (OEA) and other fatty acid ethanolamide compounds (e.g., palmitylethanolamide, elaidylethanolamide)) can reduce appetite, food intake, body weight, and body fat and alter fat metabolism.